DESCRIPTION (applicant's abstract): Erectile dysfunction is a common and personally devastating disease. Effective therapies are dependent on knowledge of the fundamental mechanisms underlying normal function. Recently, there has been considerable progress in understanding of the peripheral mechanisms of penile erections. Unfortunately, CNS mechanisms have lagged far behind. The pathways by which the hypothalamus excites the spinal erectile and ejaculatory centers remain undefined. Our laboratories have joined together to make a concerted effort at one important aspect of this CNS control. We have identified a direct hypothalamic pathway from the paraventricular nucleus to lumbosacral spinal cord as a potent facilitator of penile erection and ejaculation. The neurotransmitter for this excitation is the peptide oxytocin. We propose a broad comprehensive plan to examine the mechanism of the role of oxytocin in male sexual function. Electrophysiological studies in anesthetized rats will examine the excitation of erection and ejaculation by PVN stimulation. These will be combined with neuroanatomical staining for oxytocin and pharmacological blockade of oxytocin to verify that the effects of PVN stimulation are mediated by oxytocin. Several spinal sexual reflexes will be tested to see if they are facilitated by PVN stimulation and intrathecal administration of oxytocin. An extensive anatomical study is proposed looking at the relationship between oxytocin fibers in the lumbosacral cord and identified pelvic efferents and intereurons. Interneurons will be identified by transneuronal viral tracing, Fos staining and neurochemical identification. Our preliminary studies demonstrate that oxytocin exerts its facilitatory effects on male sexual function via a spinal nitric oxide pathway. We propose a series of pharmacological studies to examine the mechanisms of the oxytocin-nitric oxide interaction. We further propose that our results of this interdisciplinary program be validated using behavioral and pharmacological testing in unanesthetized animals.